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Isotope
Effects
Ques%ons:
What
is
the
mechanism
of
a
reac%on?
Is
a
certain
bond
broken
in
the
rate-‐determining
step?
What
is
the
transi%on
state
geometry?
Ideas:
Minimally
perturb
the
reac%on
by
isotopically
labeling
one
of
the
atoms
in
the
reactants.
Isotopic
labeling
cannot
change
the
mechanism
of
the
reac%on!
Defini%on:
The
KIE
is
the
rate
constant
ra%o,
with
the
lighter
isotopomer
in
the
numerator.
The
most
common
isotopomers
are
pro%um
and
deuterium,
but
many
other
choices
are
possible.
kH
SMH ⎯⎯
→ PDTH kH
KIE =
SMD ⎯⎯
→ PDTD
kD
kD
! !
Defini%ons
Primary
KIE:
A
bond
is
broken
or
formed
to
the
isotope
in
the
rds.
e.g.
E2
elimina%on:
HO H/D
HO(H/D) + + Cl
Cl
Secondary
KIE:
The
isotope
is
not
directly
involved
in
the
rds.
e.g.
Claisen
rearrangement:
O O
H/D
H/D
Normal
KIE:
The
lighter
isotopomer
reacts
faster:
kH/kD
>
1.0.
Inverse
KIE:
The
lighter
isotopomer
reacts
slower:
kH/kD
<
1.0.
Equilibrium
Isotope
Effect
(EIE):
The
isotope
affects
the
posi%on
of
an
equilibrium,
rather
than
the
rate
of
a
reac%on.
Primary
Isotope
Effects
kH/kD
HNO3/H2SO4 NO2
ca. 1
H*6
Hg(ClO4)2 HgClO4
H*6 6.75
OH O
HCrO4
7.7
H3C CH3 H3C CH3
H*
Origin
of
the
KIE
The
KIE
mainly
arises
from
zero
point
energy
differences.
Quantum
harmonic
oscillator
model:
The
frequency
of
the
oscillator
is:
1 k
v=
! 2π µ
k
is
the
force
constant,
which
is
how
s%ff
the
spring
is.
µ
is
the
reduced
mass,
which
is
the
effec%ve
mass
of
the
system
in
the
center
of
mass
frame:
m1m2
µ=
m1 + m2
!
Origin
of
the
KIE
⎛ 1⎞
The
energy
levels
are
given
by:
E n = ⎜ n + ⎟ hv n = 0,1,2,...
!
⎝
2 ⎠
For
n=0,
the
energy
is
0.5hv.
This
is
the
zero-‐point
energy
(ZPE).
Frequency
depends
on
reduced
mass,
so
isotopic
subs%tu%on
will
change
the
ZPE.
Since
the
ground
and
transi%on
states
contain
different
amounts
of
ZPE,
isotopic
subs%tu%on
will
change
the
reac%on
barrier.
Origin
of
the
KIE
Consider
a
homoly%c
bond
dissocia%on
of
a
C-‐H
bond:
There
is
no
ZPE
in
the
transi%on
state,
so
the
barrier
to
homolysis
will
be
equal
to
the
difference
in
zero-‐point
energy.
Because
the
lighter
isotope
has
more
ZPE,
it
has
a
smaller
barrier
and
reacts
faster.
This
means
most
KIEs
kH/kD
will
be
greater
than
1.0
(i.e.,
“normal”).
Origin
of
the
KIE
Consider
a
homoly%c
bond
dissocia%on
of
a
C-‐H
bond:
C-‐H
vs
C-‐D
stretch:
3000
cm-‐1
and
2200
cm-‐1,
a
difference
of
800
cm-‐1.
The
ZPE
difference
is
0.5*h*c*800
=
1.15
kcal/mol.
The
molar
gas
constant
is
0.002
kcal/K•mol.
At
298
K,
this
is
0.6
kcal/mol.
The
rate
difference
is
exp(–1.15/0.6)
=
6.8.
This
is
the
maximum
primary
KIE.
Origin
of
the
KIE
In
most
reac%ons,
the
bond
is
not
completely
broken
in
the
transi%on
state:
The
KIE
will
be
the
difference
between
the
ground
and
transi%on
state
ZPEs.
If
the
transi%on
state
retains
some
ZPE,
the
difference
in
ZPEs
will
be
smaller.
This
means
that
most
KIEs
will
be
less
than
6.8.
Non-‐linear
Transi%on
States
Linear
transi%on
states
have
larger
KIEs
than
non-‐linear
transi%on
states.
symmetric stretch of
A H B linear transition state:
central atom is fixed
asymmetric stretch of
H
nonlinear transition state:
central atom moves a lot
A B
When
the
central
atom
has
a
small
displacement,
the
frequency
of
the
vibra%on
will
be
hardly
affected
by
which
isotope
is
present.
The
means
the
transi%on
state
will
not
be
affected
by
the
isotope,
but
the
ground
state
will
be.
This
leads
to
a
larger
KIE.
Hammond
Postulate
In
highly
exothermic
reac%ons,
the
transi%on
state
resembles
the
star%ng
material.
This
means
bonds
are
mostly
s%ll
formed
in
the
transi%on
state.
The
difference
in
KIEs
will
be
small,
so
a
small
KIE
will
be
observed.
The
bonds
in
a
thermoneutral
reac%on
will
largely
broken,
so
larger
KIES
are
expected.
Hammond
Postulate
A
classic
example
is
from
Bruice
(JACS
1969
92
905),
who
studied
the
KIEs
of
nitroethane
deprotona%on
by
various
amines:
Amines
whose
pKa
is
closest
to
that
of
nitroethane
(8.5)
will
undergo
a
thermoneutral
deprotona%on
reac%on.
These
are
the
reac%ons
with
the
largest
KIEs.
Electronic Tuning of Enantioselectivity
Ph Ph
N N N N
Mn Mn
X O O X X O O X
Cl Cl
t-Bu t-Bu t-Bu t-Bu
X = OCH3, CH3, H, Cl, NO2
log (ratio of enantiomers)
2.0
O
n X = OMe (96% ee)
n ρ = -1.37, r = 0.989
n
n
1.0
O
X = NO2
Ar
ΔE R
X=H
O
X = MeO MnIV Ar R
X X
O O
X MnV X X MnIII X
Ar R
Basis for the Electronic Effect
H H
N N
Mn
X O O X
Cl
Ph H(D) t-Bu t-Bu Ph O H(D)
+ NaOCl
H H(D) X = OCH3, CH3, H, Cl, NO2 H H(D)
X kH / kD 5
1350 cm-1 800 cm-1
Changing
from
sp3
to
sp2
decreases
the
bend
frequency
from
1350
cm-‐1
to
800
cm-‐1.
This
means
the
transi%on
state
has
less
ZPE
than
the
ground
state
and
a
normal
SKIE
is
observed
(typical:
1.1-‐1.2).
Changing
from
sp2
to
sp3
increases
the
bend
frequency,
leading
to
an
inverse
SKIE
(typical:
0.8-‐0.9).
O H(D)
H(D) O
kH /kD = 0.95
+ O H
O
O O
Secondary
Isotope
Effects
kH/kD
OTf OAc
HOAc H* H*
H* H* 2.06
H* H* H* H*
O OH
H* H*
+ HCN CN 0.73
MeO MeO
H* H* H* H*
H2O
Cl OH 1.30
EtOH Me
Me
CH*2
H*2C 50 ºC
1.37
+
H*2C CH*2
Tunnelling
Some
reac%ons
proceed
by
passing
directly
through
the
barrier.
H/D
KIEs
of
up
to
100
can
be
observed!
Left: tunnelling in a [1,2]-shift
of a carbene, which has
a half-life of one hour at 11 K,
despite a barrier of 28 kcal.
The deuterated analog is
completely stable, which is an
infinite KIE!
-‐ The
result
is
inaccurate
because
the
error
bar
in
the
measurement
is
on
the
order
of
the
expected
isotope
effect.
Heavy
Atom
Isotope
Effects
Alterna%vely,
one
can
measure
the
rates
by
intermolecular
compe%%on:
kH ,kD
SMH + SMD ⎯⎯⎯ → PDTH + PDTD
!
That
is,
an
isotopic
mixture
of
star%ng
materials
are
reacted
in
the
same
flask,
and
the
KIE
inferred
from
the
product
distribu%on.
Specifically,
for
a
normal
KIE,
we
expect:
-‐ the
product
to
be
enriched
in
the
faster-‐reac%ng
light
isotopomer
-‐ the
star%ng
material
to
be
enrinched
in
the
slower-‐reac%ng
heavy
isotopomer
In
fact,
Singleton
has
shown
that
heavy
atom
carbon
isotope
effects
can
be
measured
for
many
reac%ons
at
natural
abundance
(JACS
1995
117
9357).
Heavy
Atom
Isotope
Effects
For
example,
consider
the
Bayer–Villiger
oxida%on
of
cyclohexanone:
O
O
O
HO O
O O R
addition migration O
+ HO
O R
This
reac%on
has
two
steps:
nucleophilic
addi%on
and
migra%on.
For
the
nucleophilic
addi%on
step,
we
expect
reac%on
to
be
slightly
faster
with
the
unlabeled
isotopomer:
O
O
HO O
O fast O R
+
HO
O R
O
O
HO O
* O slow O R
+ HO *
O R
* = 13 C label
If
we
recover
star%ng
material,
it
should
be
enriched
in
the
slower
reac%ng
13C
isotopomer.
(The
KIE
in
the
second
step
doesn’t
maner
because
the
first
step
is
irreversible.)
This
is
the
same
principle
as
that
for
kine%c
resolu%ons.
Heavy
Atom
Isotope
Effects
The
enrichment
is
related
to
the
KIE
by
the
following
equa%on:
⎛ k2 ⎞
R
( )
⎜ −1⎟
= 1− F1 ⎝ k1 ⎠
R0
!
where
R
is
the
isotopic
ra%o
in
the
recovered
star%ng
material,
R0
is
the
original
isotopic
ra%o,
1-‐F1
is
the
conversion,
and
k2/k1
is
1/KIE.
Using
quan%ta%ve
13C
and
2H
NMR:
O
1.048
0.96 H
1.003
1.00 (assumed)
0.97 H
H 1.00 (assumed)
There
is
a
large
primary
kine%c
isotope
effect
at
the
carbonyl
carbon
and
an
inverse
secondary
KIE
from
the
hybridiza%on
change
at
the
adjacent
protons.
Heavy
Atom
Isotope
Effects
If
we
apply
the
same
analysis
to
product
arer
running
the
reac%on
to
low
conversion,
we
will
find
an
en%rely
different
result!
O
H
O 1.043
1.00 (assumed)
H 1.01
0.997
These
measure
the
intramolecular
KIE!
We
are
actually
measuring
a
post-‐rate-‐
determining
selec%vity:
O
slow O
O O
rate-determining *
O addition HO O
O R
* + HO *
primary KIE
O R KIE=1
O
fast * O
either of the enantiotopic
carbons can migrate
(The
natural
abundance
of
carbon-‐13
is
1.1%,
so
we
can
assume
there
is
only
one
label
per
molecule.)